Various types of systems are known to the art for delivering biologically active agents (hereinafter "drugs") to the skin. These devices range from simple drug loaded creams, ointments and gels which are applied directly to the skin such as a nitroglycerin ointment for the treatment of angina, to more precisely controllable systems in which a drug is dispersed through a matrix of fixed configuration such as is shown in U.S. Pat. No. 3,923,939 to even more sophisticated systems which employ rate controlling membranes or other structures to precisely meter the quantity of drug that is administered through the skin for a prolonged period of time such as disclosed in U.S. Pat. Nos. 4,031,894 and 4,201,211, for example, all of which patents are incorporated herein by reference. Regardless of the actual structure of any particular system, all these systems utilize some form of a reservoir for the drug in which the drug to be dispensed is dispersed and this reservoir must have certain characteristics of viscosity, permeability, and adherence in order to render it suitable for use in a delivery system. This is particularly important in laminated systems without sealed edges such as described in the latter two patents, where the adhesive and reservoir layers must be viscous enough to prevent oozing of the layers. The latter two patents disclose mineral oil-polyisobutylene (MO-PIB) matrices for use in dispensing clonidine and scopolamine and such matrices are also useful for dispensing to the skin any moderately mineral oil soluble drug. Particularly suitable are those drugs whose solubility in mineral oil does not exceed approximately 5 mg/ml such as, in addition to clonidine and scopolamine; estradiol, phenylpropanolamine, propranolol, ouabain, salbutamol, guanabenz, labetolol, atropine, haloperidol, bromocryptine, chloropheniramine, metrifonate, isosorbide dinitrate, and nitroglycerin, for example.
In addition to the primary drug or drugs, the compositions may also contain other materials such as permeation enhancers to improve skin permeability, cytoprotective agents to reduce skin irritation, buffers to adjust pH and other materials all as is known to the art.
As disclosed in the latter two identified patents, a typical MO-PIB matrix composition will comprise a mineral oil of about 5 to 100 cp viscosity at 25.degree. C. admixed with a blend of PIBs. The MO usually constitutes between 35%-35% by weight of the mixture and the PIB can also constitute between 35%-65% of the mixture. Th PIB blend usually comprises a low molecular weight (LMW) PIB (35,000-50,000 viscosity average molecular weight) and a high molecular weight (HMW) PIB, (1,000,000 to 1,500,000 viscosity average molecular weight). Preferred mixtures comprise 35%-65% mineral oil, 10-40% LMW PIB and 10-40% HMW PIB. The precise formulation of any reservoir composition is generally adjusted to try to provide a particular combination of characteristics such as viscosity, drug permeability and adhesion as required to meet the design requirements of the end product. In general, the PIB functions as a thickener and the MO as the solvent for the drug. Thus increasing the MO/PIB ratio generally increases permeability and descreases viscosity while decreasing the MO/PIB ratio has the opposite effects. It should also be noted, as disclosed in the latter two patents, that the same general MO-PIB mixtures can be tailored to be used either as a drug reservoir or as a contact adhesive for attaching the device to the skin and the adhesive may or may not contain an amount of drug material to provide a priming dose.
Typically, the drug to be dispensed is dissolved and dispersed throughout the matrix material in amounts higher than saturation such that the reservoir contains both a dissolved and dispersed phase. The dispersed phase is normally present in amounts sufficient to maintain the concentration of the drug in matrix at or above saturation during the intended dispensing life of the device. While amounts as high as 40% by weight of drug can be included, normally a matrix for use as a drug reservoir would contain up to about 20% by weight of drug and when used as the adhesive, with a priming dose, up to about 10% by weight of drug.
In attempting to optimize matrix compositions, we have determined that the compositions should have a viscosity of no less than about 1.5.times.10.sup.7 poise and a sufficiently high permeability, DC.sub.s, for the drug to be delivered to permit adequate release rates with reasonable size skin patches. With this combination of characteristics the drug delivery systems would have excellent physical characteristics in that they would retain their structural integrity, not ooze or flow, be readily removed from the package in which they are contained, be reasonably sized and, for the laminated systems, have a sufficiently high permeability to permit the rate controlling membranes to be the predominant means for controlling the rate of drug release from the system.
It was known that the viscosity of the matrix composition could be modified by varying the MO/PIB ratio. However, increasing the viscosity by increasing the proportion of PIB results in a decrease in the permeability of the system to undesirably low levels. Correspondingly, increasing the mineral oil content to raise permeability, yields low viscosity compositions which tended to cold flow and have poor structural characteristics. Prior to our invention, for example, an MO/PIB ratio of about 1.0 was the highest feasible level for use in commercially marketable transdermal systems.
Colloidal silicon dioxide (CSD) such as Cab-O-Sil.RTM. manufactured by the Cabot Corporation and other similar colloidal silica materials are known thickeners for mineral oil (see for example, Cab-O-Sil.RTM. Properties and Functions, Cabot Corporation, 125 High St., Boston, MA 02110). It was also known by others to use CSD to thicken other types of drug matrices such as disclosed in copending, coassigned U.S. Patent Application of Gale, et al. for Novel Bandage for Administering Beneficial Drug, Ser. No. 278,364, filed Jan. 29, 1981. In addition, CSD is approved by the FDA as a material generally recognized as safe for inclusion in topical pharmaceutical preparations.
Accordingly, it was decided to use CSD to increase the viscosity of MO-PIB matrix compositions. When amounts of CSD were added to certain MO-PIB compositions, it was unexpectedly found that the viscosity could be increased without decreasing the permeability and, in fact, within certain composition ranges of the various components of the matrix composition mixture, it was possible to produce MO-PIB compositions having not only increased viscosities but also increased drug permeabilities as well. Further within certain ranges, unexpected improvements in other properties of transdermal therapeutic systems using these compositions were obtained.
Thus in the prior art systems the mechanical and diffusional properties of the system were not independently variable (i.e., an increase in permeability invariably led to a decrease in the system viscosity, and vice versa). According to our invention, however, the use of CSD in certain formulations permits these properties to be independently variable and high permeability and high viscosity are both obtainable.
It is accordingly an object of this invention to provide a matrix composition for a drug delivery system having improved properties.
It is another object of this invention to provide matrix compositions having both high viscosities and high drug permeabilities.
It is another object of this invention to provide a drug loaded MO-PIB composition having a viscosity of at least 1.5.times.10.sup.7 poise.
It is another object of this invention to provide a drug loaded matrix formed from mineral oil, PIB, CSD and a moderately mineral oil-soluble drug composition dispersed therethrough at a concentration above saturation.
It is another object of this invention to provide a rate controlled transdermal therapeutic system having a MO-PIB matrix with desired properties of viscosity, permeability and adhesion.